S26 S29 (I 992), 66, Suppl. XIX, S26-S29 Suppl. XIX,
Br. J. Cancer Br. J. Cancer (1992), 66,
'."
Macmillan Press Ltd., 1992 1992
Nausea and vomiting and cancer patients' quality of life: a discussion of Professor Selby's paper C.M. Lindley & J.D. Hirsch School of Medicine, University of North Carolina, Chapel Hill, North Carolina; Pharmacoeconomic Research, Glaxo Inc., Research Triangle Park, North Carolina, USA. Summary It is evident from the data presented above that nausea and vomiting are frequent side effects which are often persistent and distressing to patients. Evidence suggests, and intuitively it appears that avoidance of nausea and vomiting is important to the patients' ability to maintain their quality of life during the treatment period. It is of particular interest to note that in the literature reviewed in this paper standard antiemetic prescribing and practice were followed. It would, therefore, appear that available antiemetic agents are not always effective or may not be adequately employed. The toxicities associated with dopamine receptor antagonists, the current standard of antiemetic regimens, limit their usefulness in the clinical setting. In fact, the contribution of antiemetic therapy toxicities to the incidence of anxiety, fatigue, and restlessness which were commonly reported by patients in the studies reviewed should be considered. Additional effort to characterise the impact of nausea and vomiting on cancer patients' quality of life is needed. Clearly, the data available suggest that these symptoms should be included as part of the physical domain component of quality of life instruments used in cancer patients. Ideally, the instrument used should contain separate items for nausea and vomiting. Major side effects of antiemetic therapy should also be assessed since these may be as debilitating as the effects of nausea and vomiting. Increased awareness of total patient impact of emesis and antiemetic therapy will serve as an impetus for improvements in antiemetic therapy strategies and practices.
Nausea and vomiting are frequent symptoms in cancer patients. They are most commonly regarded as side effects of chemotherapy. However, nausea and vomiting are also presenting manifestations of specific cancer types. In addition, nausea and vomiting in cancer patients are often associated with fluid and electrolyte abnormalities, bowel obstruction, central nervous system metastases, and radiation therapy. The list of potential aetiologies for nausea and vomiting in cancer patients is quite lengthy and unfortunately, little is known about the pathophysiology involved. Although a myriad of antiemetic agents and regimens are available, emesis control remains imperfect and thus affects the patient's ability to maintain their quality of life during treatment. Direct analyses of the effect of nausea or vomiting has not been included in most quality of life studies in oncology. However, data from the patient care setting suggest that the impact of nausea and vomiting on quality of life is often substantial. The purpose of this paper is to present evidence which supports the existence and importance of the relationship between nausea, vomiting, and quality of life.
Incidence and duration of nausea and vomiting Incidence and duration data alone would suggest that nausea and vomiting have the potential to affect the quality of life of a significant number of cancer patients. The scope of the problem of nausea and vomiting in cancer patients was recently addressed by a National Hospice Study conducted in over 2,700 terminal cancer patients (Reuben & Mor, 1986). In this large series, 62% of terminal cancer patients developed nausea and vomiting at some time during the last 6 weeks of life with prevalence rates of at least 40%. Although only a small number of responders described these symptoms as 'horrible', more than half of those who were nauseated reported their symptoms as more severe than 'mild'. Patients with stomach and breast cancer were more likely to report nausea and vomiting. Other factors that identified patients at high risk for developing nausea and vomiting include female gender and younger age. Nausea and vomiting occurred independent of chemotherapy administration which suggests that the pathophysiologic mechanisms of chemotherapy-induced nausea and vomiting and those associated with terminal cancer may be different. Acute chemotherapy-induced nausea and vomiting (24h following chemotherapy) have been well described and are
known to be related to emetogenicity of chemotherapy, prior experience, and antiemetic regimens. Age, time of chemotherapy administration, and history of alcohol use also appear to influence occurrence of acute chemotherapy-induced emesis. The complexity of recognised independent variables makes it difficult to interpret estimates of the occurrence of nausea and vomiting. However, it appears from several published studies that nausea and vomiting are frequently present and may create formidable obstacles to optimal care of the cancer patient. Leventhal reported that 86% and 47% of breast cancer patients experienced nausea and vomiting respectively at some point during the first six cycles of chemotherapy (Leventhal et al., 1986). The average percentage of patients reporting nausea and vomiting for any given cycle was 60% and 22% respectively. Nerenz reported that nausea was present in 64% of 217 patients who were receiving their sixth cycle of chemotherapy for breast cancer or lymphoma (Nerenz et al., 1986). Acute chemotherapyinduced nausea and vomiting were reported by 50% and 27% respectively of patients in an outpatient oncology population (Lindley et al., 1989). Patients in this latter report were receiving a range of chemotherapeutic regimens that the authors classified as strong, moderate and weakly emetogenic using predetermined criteria. When only patients receiving chemotherapeutic regimens with emetogenic potential similar to that of regimens used in the Leventhal and Nerenz reports are considered, the incidence of nausea and vomiting in this study were 53% and 44% respectively. Collectively, these data suggest that despite the use of antiemetic therapy, acute nausea and vomiting are present in approximately half of all patients who receive moderate to strongly emetogenic chemotherapy regimens. Delayed nausea and vomiting (occurring up to 7 days following chemotherapy) have only recently been described. Kris et al. (1985) noted that overall 93% of patients who received high dose cisplatin experienced some degree of nausea and vomiting, commencing 24 or more hours after chemotherapy and lasting up to 120h. These effects were present in a significant number of patients who experienced no nausea and vomiting during the initial 24 h following cisplatin administration. High-dose cisplatin is clearly the most potent emetogenic regimen in common use today and is in fact the standard by which antiemetic agents are judged. However, it appears that regimens other than high-dose cisplatin also produce symptoms of delayed nausea and vomi-
NAUSEA AND VOMITING IN CANCER PATIENTS
ting. In a study by Lindley et al. (1989) overall nausea was reported by 38% and vomiting by 27% of cancer outpatients on the day following chemotherapy; and by 14% and 2% respectively 5 days following chemotherapy administration. The emetogenic potential of the chemotherapeutic regimen, significantly influenced both incidence and duration, and the incidence and duration were much higher than the overall group mean in those patients who received moderate to strongly emetogenic regimens. Interestingly, 33% of patients who reported nausea and 55% of patients who experienced vomiting at any point during the 5 day study period experienced delayed symptoms only. Nausea and vomiting persisting beyond a 24 h period of observation has been anecdotally reported in two acute antiemetic trials (Fetting et al., 1982; Strumm et al., 1984). Cyclophosphamide and doxorubicin were the chemotherapeutic agents associated with delayed nausea and vomiting in these reports. Anticipatory nausea and vomiting, defined as nausea and vomiting starting before the administration of chemotherapy in patients with past poor antiemetic control, is now recognised as a legitimate entity in the epidemiology of chemotherapy-induced nausea and vomiting. Anticipatory nausea and vomiting has been reported to occur in up to 20 to 50% of cancer patients. Variables that have been correlated with anticipatory nausea and vomiting include: age >50 years; susceptibility to motion sickness; moderate, severe, or intolerable nausea and vomiting, with previous courses; and symptoms of sweating, warmth/flushing, generalised weakness with previous therapy (Morrow, 1984). Nausea and vomiting which occur outside of the classic context, i.e. in no direct relationship to cytotoxic agents, are often not appreciated as nausea and vomiting associated with treatment. Therefore, the consequences of this aetiologic factor may in fact be underestimated. However, it is well recognised that conditioned reflexes contributing to nausea and vomiting in cancer patients are often not amenable to conventional antiemetic therapy. This underscores the need to adequately prevent nausea and vomiting associated with administration of cytotoxics as opposed to relying on management of these symptoms once they occur.
Medical consequences associated with chemotherapy-induced nausea and vomiting The consequences of inadequate emesis control range from patient distress and discomfort which will be discussed in a subsequent section, to physiologic complications and decreased patient compliance with treatment. Physiological complications include oesophageal tears, skeletal fractures, wound dehiscence, and malnutrition, all of which may complicate or compromise subsequent therapy as well as impact upon the patient's quality of life. In addition, the metabolic consequences of vomiting (e.g. chloride, potassium, volume depletion; and metabolic alkalosis) may be quite dangerous in that they provide an environment that can exacerbate the nephrotoxicity of chemotherapeutic, antibiotic and antifungal agents. The effect of nausea and vomiting on patient compliance with treatment has been reported by a number of researchers. Turbow and co-workers (Turbow et al., 1980), reported that 7% of patients receiving a combination of cisplatin and hexamethylmelamine for ovarian cancer required hospitalisation because of vomiting and refused further treatment. Among 68 patients undergoing treatment with various cytotoxic drugs, Shulz (1980) reported that 31% had nausea and vomiting before and during treatment and 10% either stopped treatment or required dose reduction. Twenty-five per cent of 80 breast cancer patients studied by Wampler were reported to be noncompliant due to severe nausea and vomiting (Wampler et al., 1980). Taylor et al. (1980) reported that one-third of patients with testicular carcinoma refused or deferred treatment because of depression or gastrointestinal toxicity. The increasingly recognised relationship between drug dose per unit time and therapeutic outcome coupled with the fact that many patients are reported to refuse or delay potentially curative treatment due
S27
to nausea and vomiting, underscores the need for better emesis management.
Impact of chemotherapy-induced nausea and vomiting on patients' quality of life To evaluate the risk vs benefit associated with the use of chemotherapy in the treatment of cancer it is important to recognise the effect of treatment on the host, as well as on the disease. The likelihood of side effects and their potential to increase emotional distress, disrupt daily activities and impact on the patients' overall quality of life must be addressed. The incidence and duration of nausea and vomiting have been described above. A limited number of investigators have studied the patients' perception of the impact of chemotherapy-induced side effects, including nausea and vomiting. Nausea and vomiting were ranked as the most severe overall side effects experienced in a survey of 99 patients with advanced cancer receiving chemotherapy (Coates et al., 1983). Additional physical symptoms ranked as severe included loss of hair, fatigue, anxiety, tenseness, and difficulty sleeping. Non-physical side effects constituted 54% of the most severe symptoms and included the thought of coming for treatment, the length of time taken by treatment and having a needle in place. Differences in ranking of severity of side effects varied with patient characteristics as well as by diagnosis, treatment and response. The authors concluded that evaluation of patient perception of the severity of side effects was an aid to assessing the cost benefit balance when deciding to use chemotherapy in individual patients. A study by Silberfarb et al. (1980), examined the percentage of women with breast cancer who experienced moderate to severe impairment associated with a number of physical symptoms occurring secondary to treatment. In the women receiving chemotherapy, 43% reported that nausea resulted in moderate to severe physical impairment. This percentage was greater or equal to all other symptoms/impairments cited except energy, pain, and hair loss. In a recently reported study, Love et al. (1989) measured occurrence of chemotherapy side effects and patient distress in 238 patients with breast cancer or lymphoma. Participants were interviewed at five points during their six cycles of therapy. Nausea, hair loss, and tiredness were reported by more than 80% of patients, vomiting was reported by 54% of patients. The relationship between individual side effects and difficulty and distress from chemotherapy were assessed using standard scales. Nausea and vomiting each emerged as important predictors of patient distress and difficulty. Among patients with nausea, ratings of overall treatment distress and difficulty were significantly higher if nausea lasted more than 24 h. Tiredness, weakness and diarrhoea were also significantly correlated with difficulty of treatment. The relationship of occurrence of side effects, 'disruption of social life' and 'disruption of work life' was also assessed. Nausea and vomiting were significantly correlated with these scales where as the relationship with other common side effects such as diarrhoea, mouth sores, tiredness or weakness were either inconsistent or non-existent. The relationship of distress caused by chemotherapy, and disruption of work and social life with total number of side effects experienced was consistently greater than that observed with each side effect individually. Thus, a cumulative effect of side effects on the patients' daily function is suggested. Assessment of the relationship between nausea and vomiting and overall disruption in patients' life was included in a study of Meyerwitz et al. (1979). Of 50 women receiving adjuvant chemotherapy for Stage II breast cancer, 88% reported nausea as a side effect which had a major disruptive influence on their life. This percentage was second only to fatigue (96%). Almost one-third (28%) of these patients reported that vomiting had a major disruptive influence on their life. The results outlined above illustrate the impact of nausea and vomiting on single dimensions of quality of life (physical,
S28
C.M. LINDLEY & J.D. HIRSCH Table I Questions related to nausea and vomiting in selected quality of life
instruments
Questionnaire Cancer specific Ability Index Breast Cancer Chemotherapy Questionnaire CARES. Chemotherapy CARES. Radiation Quality of Life Index. Padilla et al. EORTC Core FACT Functional Living Index. Cancer Functional Living Index. Emesis LASA: Breast Cancer Ferrans & Power Quality of Life index: Cancer Version Southwest Oncology Group Quality of Life Questionnaire for Prostate Cancer Quality of Life Index (Spitzer) General McMaster Health Index MOS.36 Rotterdam Symptom Checklist Sickness Impact Profile Profile of Moods State
psychological and social function). Studies which consider the impact of nausea and vomiting on a broader, multidimensional measure of quality of life are lacking. Many available quality of life instruments include questions related to nausea and vomiting. Table I presents a summary of the occurrence of nausea and vomiting questions in quality of life instruments frequently used in oncology. As would be expected, instruments which are cancer specific frequently include nausea and vomiting questions. However, it is of interest to note than many cancer specific instruments do not contain nausea or vomiting questions. In addition, some instruments only ask a combined question to assess both side effects, or focus only on nausea. Since nausea and vomiting are distinct side effects with differing incidence, duration, and perceived severity, optimal instruments for oncology would include separate items. We recently examined the impact of chemotherapy-induced emesis on patients' quality of life using a multi-dimensional instrument with explicit nausea and vomiting questions (Lindley et al., unpublished observations). In this study, 140 outpatients receiving chemotherapy were surveyed over an 8 week period. Two instruments, Functional Living Index Cancer (FLIC) and the Functional Living Index - Emesis
Number of questions on: Combined nausea and Nausea Vomiting vomiting 1 2
-
-
-
1 1 1 2 9
1 1 -
I 2
1
-
9
-
-
-
-
2
-
-
-
1
1
2
-
(FLIE) were administered prior to and 3 days after chemotherapy. The FLIC is a multi-dimensional (physical well being and ability, emotional state, sociability, family situation and nausea) quality of life instrument. The FLIE was modeled after the FLIC but was specifically designed to assess the impact of nausea and vomiting on multiple dimensions of the patient's life. A decrease in FLIC and FLIE scores indicated that all patients experienced an acute decline in their quality of life during the immediate treatment period. However, the decline experienced by patients with nausea and vomiting was significantly greater than for those who did not experience these treatment toxicities. Examination of the items contained in the FLIE indicated that patients who experienced emesis were also less able to maintain their daily activities than patients who did not experience emesis. Of those patients reporting emesis, 23% were unable to go to work, 22% were unable to prepare meals, and 12% were unable to take prescribed medications specifically because of emesis. These preliminary results indicate the importance of examining the impact of nausea and vomiting on the patients' overall quality of life, particularly as treatments are increasingly performed on an outpatient basis.
References
CLARK, R.A., KRIS, M.G., GRALLA, R.J. & 4 others (1985). Incidence, course and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J. Clin. Oncol., 3, 1379. COATES, A., ABRAHAM, S., KAYE, S.B. & 4 others (1983). On the receiving end - patient perception of the side effects of cancer chemotherapy. Eur. J. Cancer Clin. Oncol., 19, 203. FETTING, J.H., GRUCHOW, L.B., FULSTEIN, M.F. et al. (1982). The course of nausea and vomiting after high-dose cyclophosphamide. Cancer Treatment Rep., 66, 1487. LEVENTHAL, H., EASTERLING, D.V., COONS, H.L., LUCHTERHAND,
C.M. & LOVE, P.R. (1986). Adaptation to Chemotherapy Treatments. In Andersen, B.L. (ed.) Women with Cancer, New York: Springer-Verlag, pp. 172. LINDLEY, C.M., BERNARD, S. & FIELDS, S.M. (1987). Incidence and duration of chemotherapy-induced nausea and vomiting in the outpatient oncology population. J. Clin. Oncol., 7, 1142.
LOVE, R.R., LEVENTHAL, H., DOUGLAS, V. et al. (1989). Side effects and emotional distress during cancer chemotherapy. Cancer, 63, 604. MEYEROWITZ, B.E., SPARKS, F.C. & SPEARS, I.K. (1979). Adjuvant chemotherapy for breast carcinoma, psychosocial implications. Cancer, 43, 1613. MORROW, G.R. (1984). Clinical characteristics associated with the development of anticipatory nausea and vomiting in cancer patients. J. Clin. Oncol., 2, 1170. NERENZ, D., LOVE, R.R., LEVENTHAL, H. & EASTERLING, D.V.
(1986). Psychosocial consequences of cancer chemotherapy for elderly patients. Health Serv. Res., 20, 961. REUBEN, D.B. & MOR, V. (1986). Nausea and vomiting in tenninal cancer patients, National Hospice Study. Arch. Intern. Med., 146, 2021.
NAUSEA AND VOMITING IN CANCER PATIENTS SCHULTZ, L.S. (1980). Classical (Pavlovian) conditioning of nausea and vomiting in cancer chemotherapy. Proc. A.A.C.R.A.S.C.O., 21, 381. SILBERFARB, P.M., MAURER, H.L. & CROWTHAMEL, G. (1980). Psychosocial aspects of neoplastic disease: I. Functional status of breast cancer patients during different treatment regimens. Am. J. Psychiatry, 137, 450. STRUM, S.B., McDERMED, J.E., PILEGGI, J. & others (1984). Intravenous metoclopramide prevention of chemotherapy-induced nausea and vomiting. Cancer, 53, 1432. TAYLOR, H.G., BROWN, A.W. & BUTrER, W.B. & others (1980). Modification of VAB III in the treatment of patients with stage II and stage III nonseminomatous germ cell centre. Proc. A.A.C. R.A.S.C.O., 21, 432.
S29
TURBOW, M.M., JONES, H., FRIEDMAN, H. & others (1980). Chemotherapy of ovarian carcinoma: Hexamethylmelamine (HMM) and cis-platinum for patients with persistent disease who fail alkylating agent and adriamycin therapy. Proc. A.A.C.R.A. S.C.O., 21, 361. WAMPLER, G.L., SHULZ, J.J., ESSIG, L.J. & others (1980). Virginia Oncology Group Surgical Adjuvant Treatment Breast Carcinoma: A Preliminary Report. Proc. A.A.C.R.A.S.C.O., 21, 412.
Br. J. Cancer Br. J. Cancer (1992), 66,
'."
Macmillan Press Ltd., 1992 1992
Nausea and vomiting and cancer patients' quality of life: a discussion of Professor Selby's paper C.M. Lindley & J.D. Hirsch School of Medicine, University of North Carolina, Chapel Hill, North Carolina; Pharmacoeconomic Research, Glaxo Inc., Research Triangle Park, North Carolina, USA. Summary It is evident from the data presented above that nausea and vomiting are frequent side effects which are often persistent and distressing to patients. Evidence suggests, and intuitively it appears that avoidance of nausea and vomiting is important to the patients' ability to maintain their quality of life during the treatment period. It is of particular interest to note that in the literature reviewed in this paper standard antiemetic prescribing and practice were followed. It would, therefore, appear that available antiemetic agents are not always effective or may not be adequately employed. The toxicities associated with dopamine receptor antagonists, the current standard of antiemetic regimens, limit their usefulness in the clinical setting. In fact, the contribution of antiemetic therapy toxicities to the incidence of anxiety, fatigue, and restlessness which were commonly reported by patients in the studies reviewed should be considered. Additional effort to characterise the impact of nausea and vomiting on cancer patients' quality of life is needed. Clearly, the data available suggest that these symptoms should be included as part of the physical domain component of quality of life instruments used in cancer patients. Ideally, the instrument used should contain separate items for nausea and vomiting. Major side effects of antiemetic therapy should also be assessed since these may be as debilitating as the effects of nausea and vomiting. Increased awareness of total patient impact of emesis and antiemetic therapy will serve as an impetus for improvements in antiemetic therapy strategies and practices.
Nausea and vomiting are frequent symptoms in cancer patients. They are most commonly regarded as side effects of chemotherapy. However, nausea and vomiting are also presenting manifestations of specific cancer types. In addition, nausea and vomiting in cancer patients are often associated with fluid and electrolyte abnormalities, bowel obstruction, central nervous system metastases, and radiation therapy. The list of potential aetiologies for nausea and vomiting in cancer patients is quite lengthy and unfortunately, little is known about the pathophysiology involved. Although a myriad of antiemetic agents and regimens are available, emesis control remains imperfect and thus affects the patient's ability to maintain their quality of life during treatment. Direct analyses of the effect of nausea or vomiting has not been included in most quality of life studies in oncology. However, data from the patient care setting suggest that the impact of nausea and vomiting on quality of life is often substantial. The purpose of this paper is to present evidence which supports the existence and importance of the relationship between nausea, vomiting, and quality of life.
Incidence and duration of nausea and vomiting Incidence and duration data alone would suggest that nausea and vomiting have the potential to affect the quality of life of a significant number of cancer patients. The scope of the problem of nausea and vomiting in cancer patients was recently addressed by a National Hospice Study conducted in over 2,700 terminal cancer patients (Reuben & Mor, 1986). In this large series, 62% of terminal cancer patients developed nausea and vomiting at some time during the last 6 weeks of life with prevalence rates of at least 40%. Although only a small number of responders described these symptoms as 'horrible', more than half of those who were nauseated reported their symptoms as more severe than 'mild'. Patients with stomach and breast cancer were more likely to report nausea and vomiting. Other factors that identified patients at high risk for developing nausea and vomiting include female gender and younger age. Nausea and vomiting occurred independent of chemotherapy administration which suggests that the pathophysiologic mechanisms of chemotherapy-induced nausea and vomiting and those associated with terminal cancer may be different. Acute chemotherapy-induced nausea and vomiting (24h following chemotherapy) have been well described and are
known to be related to emetogenicity of chemotherapy, prior experience, and antiemetic regimens. Age, time of chemotherapy administration, and history of alcohol use also appear to influence occurrence of acute chemotherapy-induced emesis. The complexity of recognised independent variables makes it difficult to interpret estimates of the occurrence of nausea and vomiting. However, it appears from several published studies that nausea and vomiting are frequently present and may create formidable obstacles to optimal care of the cancer patient. Leventhal reported that 86% and 47% of breast cancer patients experienced nausea and vomiting respectively at some point during the first six cycles of chemotherapy (Leventhal et al., 1986). The average percentage of patients reporting nausea and vomiting for any given cycle was 60% and 22% respectively. Nerenz reported that nausea was present in 64% of 217 patients who were receiving their sixth cycle of chemotherapy for breast cancer or lymphoma (Nerenz et al., 1986). Acute chemotherapyinduced nausea and vomiting were reported by 50% and 27% respectively of patients in an outpatient oncology population (Lindley et al., 1989). Patients in this latter report were receiving a range of chemotherapeutic regimens that the authors classified as strong, moderate and weakly emetogenic using predetermined criteria. When only patients receiving chemotherapeutic regimens with emetogenic potential similar to that of regimens used in the Leventhal and Nerenz reports are considered, the incidence of nausea and vomiting in this study were 53% and 44% respectively. Collectively, these data suggest that despite the use of antiemetic therapy, acute nausea and vomiting are present in approximately half of all patients who receive moderate to strongly emetogenic chemotherapy regimens. Delayed nausea and vomiting (occurring up to 7 days following chemotherapy) have only recently been described. Kris et al. (1985) noted that overall 93% of patients who received high dose cisplatin experienced some degree of nausea and vomiting, commencing 24 or more hours after chemotherapy and lasting up to 120h. These effects were present in a significant number of patients who experienced no nausea and vomiting during the initial 24 h following cisplatin administration. High-dose cisplatin is clearly the most potent emetogenic regimen in common use today and is in fact the standard by which antiemetic agents are judged. However, it appears that regimens other than high-dose cisplatin also produce symptoms of delayed nausea and vomi-
NAUSEA AND VOMITING IN CANCER PATIENTS
ting. In a study by Lindley et al. (1989) overall nausea was reported by 38% and vomiting by 27% of cancer outpatients on the day following chemotherapy; and by 14% and 2% respectively 5 days following chemotherapy administration. The emetogenic potential of the chemotherapeutic regimen, significantly influenced both incidence and duration, and the incidence and duration were much higher than the overall group mean in those patients who received moderate to strongly emetogenic regimens. Interestingly, 33% of patients who reported nausea and 55% of patients who experienced vomiting at any point during the 5 day study period experienced delayed symptoms only. Nausea and vomiting persisting beyond a 24 h period of observation has been anecdotally reported in two acute antiemetic trials (Fetting et al., 1982; Strumm et al., 1984). Cyclophosphamide and doxorubicin were the chemotherapeutic agents associated with delayed nausea and vomiting in these reports. Anticipatory nausea and vomiting, defined as nausea and vomiting starting before the administration of chemotherapy in patients with past poor antiemetic control, is now recognised as a legitimate entity in the epidemiology of chemotherapy-induced nausea and vomiting. Anticipatory nausea and vomiting has been reported to occur in up to 20 to 50% of cancer patients. Variables that have been correlated with anticipatory nausea and vomiting include: age >50 years; susceptibility to motion sickness; moderate, severe, or intolerable nausea and vomiting, with previous courses; and symptoms of sweating, warmth/flushing, generalised weakness with previous therapy (Morrow, 1984). Nausea and vomiting which occur outside of the classic context, i.e. in no direct relationship to cytotoxic agents, are often not appreciated as nausea and vomiting associated with treatment. Therefore, the consequences of this aetiologic factor may in fact be underestimated. However, it is well recognised that conditioned reflexes contributing to nausea and vomiting in cancer patients are often not amenable to conventional antiemetic therapy. This underscores the need to adequately prevent nausea and vomiting associated with administration of cytotoxics as opposed to relying on management of these symptoms once they occur.
Medical consequences associated with chemotherapy-induced nausea and vomiting The consequences of inadequate emesis control range from patient distress and discomfort which will be discussed in a subsequent section, to physiologic complications and decreased patient compliance with treatment. Physiological complications include oesophageal tears, skeletal fractures, wound dehiscence, and malnutrition, all of which may complicate or compromise subsequent therapy as well as impact upon the patient's quality of life. In addition, the metabolic consequences of vomiting (e.g. chloride, potassium, volume depletion; and metabolic alkalosis) may be quite dangerous in that they provide an environment that can exacerbate the nephrotoxicity of chemotherapeutic, antibiotic and antifungal agents. The effect of nausea and vomiting on patient compliance with treatment has been reported by a number of researchers. Turbow and co-workers (Turbow et al., 1980), reported that 7% of patients receiving a combination of cisplatin and hexamethylmelamine for ovarian cancer required hospitalisation because of vomiting and refused further treatment. Among 68 patients undergoing treatment with various cytotoxic drugs, Shulz (1980) reported that 31% had nausea and vomiting before and during treatment and 10% either stopped treatment or required dose reduction. Twenty-five per cent of 80 breast cancer patients studied by Wampler were reported to be noncompliant due to severe nausea and vomiting (Wampler et al., 1980). Taylor et al. (1980) reported that one-third of patients with testicular carcinoma refused or deferred treatment because of depression or gastrointestinal toxicity. The increasingly recognised relationship between drug dose per unit time and therapeutic outcome coupled with the fact that many patients are reported to refuse or delay potentially curative treatment due
S27
to nausea and vomiting, underscores the need for better emesis management.
Impact of chemotherapy-induced nausea and vomiting on patients' quality of life To evaluate the risk vs benefit associated with the use of chemotherapy in the treatment of cancer it is important to recognise the effect of treatment on the host, as well as on the disease. The likelihood of side effects and their potential to increase emotional distress, disrupt daily activities and impact on the patients' overall quality of life must be addressed. The incidence and duration of nausea and vomiting have been described above. A limited number of investigators have studied the patients' perception of the impact of chemotherapy-induced side effects, including nausea and vomiting. Nausea and vomiting were ranked as the most severe overall side effects experienced in a survey of 99 patients with advanced cancer receiving chemotherapy (Coates et al., 1983). Additional physical symptoms ranked as severe included loss of hair, fatigue, anxiety, tenseness, and difficulty sleeping. Non-physical side effects constituted 54% of the most severe symptoms and included the thought of coming for treatment, the length of time taken by treatment and having a needle in place. Differences in ranking of severity of side effects varied with patient characteristics as well as by diagnosis, treatment and response. The authors concluded that evaluation of patient perception of the severity of side effects was an aid to assessing the cost benefit balance when deciding to use chemotherapy in individual patients. A study by Silberfarb et al. (1980), examined the percentage of women with breast cancer who experienced moderate to severe impairment associated with a number of physical symptoms occurring secondary to treatment. In the women receiving chemotherapy, 43% reported that nausea resulted in moderate to severe physical impairment. This percentage was greater or equal to all other symptoms/impairments cited except energy, pain, and hair loss. In a recently reported study, Love et al. (1989) measured occurrence of chemotherapy side effects and patient distress in 238 patients with breast cancer or lymphoma. Participants were interviewed at five points during their six cycles of therapy. Nausea, hair loss, and tiredness were reported by more than 80% of patients, vomiting was reported by 54% of patients. The relationship between individual side effects and difficulty and distress from chemotherapy were assessed using standard scales. Nausea and vomiting each emerged as important predictors of patient distress and difficulty. Among patients with nausea, ratings of overall treatment distress and difficulty were significantly higher if nausea lasted more than 24 h. Tiredness, weakness and diarrhoea were also significantly correlated with difficulty of treatment. The relationship of occurrence of side effects, 'disruption of social life' and 'disruption of work life' was also assessed. Nausea and vomiting were significantly correlated with these scales where as the relationship with other common side effects such as diarrhoea, mouth sores, tiredness or weakness were either inconsistent or non-existent. The relationship of distress caused by chemotherapy, and disruption of work and social life with total number of side effects experienced was consistently greater than that observed with each side effect individually. Thus, a cumulative effect of side effects on the patients' daily function is suggested. Assessment of the relationship between nausea and vomiting and overall disruption in patients' life was included in a study of Meyerwitz et al. (1979). Of 50 women receiving adjuvant chemotherapy for Stage II breast cancer, 88% reported nausea as a side effect which had a major disruptive influence on their life. This percentage was second only to fatigue (96%). Almost one-third (28%) of these patients reported that vomiting had a major disruptive influence on their life. The results outlined above illustrate the impact of nausea and vomiting on single dimensions of quality of life (physical,
S28
C.M. LINDLEY & J.D. HIRSCH Table I Questions related to nausea and vomiting in selected quality of life
instruments
Questionnaire Cancer specific Ability Index Breast Cancer Chemotherapy Questionnaire CARES. Chemotherapy CARES. Radiation Quality of Life Index. Padilla et al. EORTC Core FACT Functional Living Index. Cancer Functional Living Index. Emesis LASA: Breast Cancer Ferrans & Power Quality of Life index: Cancer Version Southwest Oncology Group Quality of Life Questionnaire for Prostate Cancer Quality of Life Index (Spitzer) General McMaster Health Index MOS.36 Rotterdam Symptom Checklist Sickness Impact Profile Profile of Moods State
psychological and social function). Studies which consider the impact of nausea and vomiting on a broader, multidimensional measure of quality of life are lacking. Many available quality of life instruments include questions related to nausea and vomiting. Table I presents a summary of the occurrence of nausea and vomiting questions in quality of life instruments frequently used in oncology. As would be expected, instruments which are cancer specific frequently include nausea and vomiting questions. However, it is of interest to note than many cancer specific instruments do not contain nausea or vomiting questions. In addition, some instruments only ask a combined question to assess both side effects, or focus only on nausea. Since nausea and vomiting are distinct side effects with differing incidence, duration, and perceived severity, optimal instruments for oncology would include separate items. We recently examined the impact of chemotherapy-induced emesis on patients' quality of life using a multi-dimensional instrument with explicit nausea and vomiting questions (Lindley et al., unpublished observations). In this study, 140 outpatients receiving chemotherapy were surveyed over an 8 week period. Two instruments, Functional Living Index Cancer (FLIC) and the Functional Living Index - Emesis
Number of questions on: Combined nausea and Nausea Vomiting vomiting 1 2
-
-
-
1 1 1 2 9
1 1 -
I 2
1
-
9
-
-
-
-
2
-
-
-
1
1
2
-
(FLIE) were administered prior to and 3 days after chemotherapy. The FLIC is a multi-dimensional (physical well being and ability, emotional state, sociability, family situation and nausea) quality of life instrument. The FLIE was modeled after the FLIC but was specifically designed to assess the impact of nausea and vomiting on multiple dimensions of the patient's life. A decrease in FLIC and FLIE scores indicated that all patients experienced an acute decline in their quality of life during the immediate treatment period. However, the decline experienced by patients with nausea and vomiting was significantly greater than for those who did not experience these treatment toxicities. Examination of the items contained in the FLIE indicated that patients who experienced emesis were also less able to maintain their daily activities than patients who did not experience emesis. Of those patients reporting emesis, 23% were unable to go to work, 22% were unable to prepare meals, and 12% were unable to take prescribed medications specifically because of emesis. These preliminary results indicate the importance of examining the impact of nausea and vomiting on the patients' overall quality of life, particularly as treatments are increasingly performed on an outpatient basis.
References
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